Voriconazole is a broad spectrum antifungal agent. Patients with acute myeloid leukemia that are susceptible to fungal infections receive simultaneously voriconazole and antitumor regimens. Drug-drug interactions between voriconazole and cytarabine involving the CYP3A4 enzyme are thought to affect the pharmacokinetic profile of the drugs and as a result their toxicological or pharmacological outcome. Population pharmacokinetic models were used to characterize these interactions and optimize the dose schemes after coadministration. Simulations and estimations were conducted by using NONMEM. The optimal dose for one hour intravenous infusion of voriconazole was estimated to 5mg/h. The proposed time points based on the pharmacokinetic profile of voriconazole for validated the model by using a small cohort of patients are 2h, 26h, 27h, 50h, 51h, 120h, 335h, 336h after the first administration of the antifungal agent. / Η βορικοναζόλη αποτελεί έναν ευρέως φάσματος αντιμυκητιασικό παράγοντα. Ασθενείς με οξεία μυελογενή λευχαιμία (ΟΜΛ) που θεωρούνται ευπαθείς στην ανάπτυξη μυκητιάσεων λαμβάνουν βορικοναζόλη σε συγχορήγηση με τα αντικαρκινικά φάρμακα. Αλληλεπιδράσεις φαρμάκων που λαμβάνουν χώρα κατά την διάρκεια του μεταβολισμού των χρησιμοποιούμενων φαρμάκων από κοινά ισοένζυμα του κυττοχρώματος P450 πιθανότατα να επιρεάζουν το φαρμακοκινητικό προφίλ τών φαρμάκων. Πληθυσμιακά φαρμακοκινητικά μοντέλα χρησιμοποιήθηκαν για τον χαρακτηρισμό αυτών των αλληλεπιδράσεων και την βελτιστοποίηση του δοσολογικού σχήματος. Προσομοιώσεις και υπολογισμοί πραγματοποιήθηκαν μέσω του προγράμματος NONMEM. Η βέλτιστη δόση μετά μια ώρα έγχυσης της βορικοναζόλης είναι 5mg/L. Τα προτεινόμενα χρονικά σημεία βασισμένα στο φαρμακοκινητικό προφίλ της βορικοναζόλης για την διεξάγωγή μικρού μήκους κλινικής μελέτης που θα επιτρέψει την αξιολόγηση του μοντέλου είναι 2h, 26h, 27h, 50h, 51h, 120h, 335h, 336h μετά την χορήγηση του αντιμυκητιασικού φαρμάκου.

Στην παρούσα διπλωματική εργασία, πραγματοποιείται μία εκτεταμένη βιβλιογραφική αναφορά των πιο γνωστών και ευρέως χρησιμοποιούμενων μεθόδων για τον έλεγχο του βάθους της αναισθησίας (DoA) σε ασθενείς. Αν και ο χειροκίνητος έλεγχος της αναισθησίας παραμένει ο πιο διαδεδομένος τρόπος κατά τη διάρκεια των χειρουργικών επεμβάσεων, έχει πραγματοποιηθεί μία πληθώρα ερευνών και δοκιμών προκειμένου να αυτοματοποιηθεί η συγκεκριμένη διαδικασία. Στις περισσότερες μάλιστα από αυτές χρησιμοποιούνται μοντέλα PID ελεγκτών. Προκειμένου να επιτευχθούν καλύτερα επίπεδα εμπιστοσύνης και ακρίβειας, έχουν προταθεί διαφορετικοί τρόποι αντιμετώπισης που εφαρμόζονται πλέον σε ρεαλιστικά μοντέλα ασθενών. Επομένως, στη συγκεκριμένη εργασία γίνεται αναφορά στα διάφορα υπολογιστικά συστήματα που χρησιμοποιούνται επί του παρόντος για την υλοποίηση αλγορίθμων προβλεπτικού ελέγχου, περιγράφεται με λεπτομέρειες ο τρόπος εξαγωγής των Φαρμακοκινητικών και Φαρμακοδυναμικών μοντέλων, καθώς και επίσης μελετάται ο τρόπος λειτουργίας και η απόδοση διάφορων ελεγκτών, όπως απλός PID, MPC, RTDA και ενός deadbeat ελεγκτή, με σκοπό την εξομάλυνση της ύπνωσης έχοντας ως κύρια μεταβλητή ελέγχου την προποφόλη. / In this diploma thesis, there is an extended literature review of the most known and used methods for the depth of anesthesia (DoA) control systems. Although manual control of anesthesia is still the dominant practice during surgery, an increasing number of studies have been conducted to investigate the possibility of automating this procedure. These studies used proportional−integral−derivative (PID) controllers, as well as model-based controllers. However, there is a need for a comprehensive evaluation of closed-loop systems, to establish their safety, reliability, and efficacy for anesthesia regulation. This requires a detailed evaluation of promising and/or recent controllers for a range of patients and conditions via simulation. The present study investigates the different computational systems that are used to implement the appropriate algorithms for MPC ,the mathematic model of Pharmacokinetics and Pharmacodynamics models and the performance of single-loop PID, MPC, RTDA (Robustness, set point Tracking, Disturbance rejection, Aggressiveness) and deadbeat controllers for closed-loop regulation of hypnosis using propofol with bi spectral index (BIS) as the controlled variable

Artemisinins are known for their low aqueous solubility and resultant poor and erratic absorption upon oral administration. The poor solubility and erratic absorption usually translate, to low bibavailability. Enzymatic degradation and physiological barriers are also amongst the challenges which must be overcome to ensure effective delivery. Artemisininbased monotherapy and combination therapies are essential for the management and treatment of uncomplicated as well as cerebral malaria. Artemisone and artemiside are novel artemisinin derivatives, their antimalarial activity/efficacy was evaluated in vitro and in vivo in the presence and absence of Pheroid™ technology. Pheroid™ technology is a patented drug delivery system which has the ability to capture, transport and deliver pharmacologically active compounds. Pharmacokinetic models were also constructed for artemis one and artemiside, both in the presence and absence of Pheroid™ technology. Results obtained with the jn vitro antimalarial activity evaluation indicated that artemiside was slightly more potent than artemisone and much more potent than artesunate. Artemiside had IC50 values of 0.54 ± 0.03 nM (reference) and 0.10 ± 0.05 nM (Pheroid™) (p = 0.009) while artemisone had values of 0.94 ± 0.04 nM (reference) and 0.21 ± 0.04 nM (Pheroid™) (p = 0.0001). Artesunate had IC50 values of 29.65 ± 0.05 nM (reference) and 10.20 ± 0.04 nM (Pheroid™) (p < 0.0001). Results obtained with the in vivo antimalarial activity evaluation indicated that artemisone led to more favourable treatment outcomes than artemiside. The Peters' 4-day suppressive test was used as a basis model. With artemisone treatment recrudescence occured at 16 days post infection at a dose of 20.0 mg/kg bodyweight and at 12 days post infection at 2.5 mg/kg bodyweight. With artemiside recrudescence occurred at 8 days post infection with both the 10.0 mg/kg and 2.5 mg/kg bodyweight treatment regimens. When comparing the antimalarial effect of the drugs with and without Pheroid™ technology there was no significant difference in terms of parasite reduction or in the achieved treatment outcomes of either compounds. The pharmacokinetic parameters were evaluated in a mouse model where C57 BL6 mice were used. The compounds were administered at a dose of 50.0 mg/kg bodyweight via an oral gavage tube at a volume of 200 µl. Blood samples were collected by means of tail bleeding. Sensitive and selective LC/MS/MS methods were developed to analyze the drug concentrations in the plasma samples. The relative bioavailability of artemisone was RA = 1.0 (reference) and RA = 4.57 (Pheroid™) (p < 0.001). The absolute bioavailability was calculated as F = 0.10 (reference) and F = 0.48(Pheroid™) (p < 0.001). The boiavailability of artemiside was not dramatically enhanced by the Pheroid™ delivery system. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Human milk contains ~ 25 µg/mL of soluble cluster of differentiation 14 (sCD14) protein, a pattern recognition receptor (PRR) that triggers the innate immune system to respond to bacterial lipopolysaccharide (LPS). To date, the role of CD14 in the digestive tract of breast fed infants has not been well characterized and is the subject of this thesis. To investigate the biodistribution of proteins such as CD14 in vivo, a novel method for 14C radiolabeling of proteins to high specific radioactivity was developed using in vacuo methylation. Bovine serum albumin (BSA) and casein were used as test proteins to determine the following: 1) The efficacy of the in vacuo radiolabeling procedure; 2) The extent of incorporation of the 14C-label into the organs of oro-gastric gavaged 10 day old Sprague Dawley rats. [14C]BSA, [14C]casein and [14C]CD14 were prepared with specific radioactivities of 10 400, 10 800 and 163 000 dpm/µg, respectively. After feeding 6.25 µg of 14C-labeled proteins, quantifiable levels of 14C were found in the stomach, jejunum, duodenum, ileum, large intestine, intestinal luminal flushes, blood, liver, spleen and kidneys of rats. The accumulation of radiolabel in the organs of [14C]CD14 fed rats was temporally and spatially distinct from [14C]BSA and [14C]casein. Most notably, the label persisted in the stomach 480 min post-gavage. To design a neonate animal model for biodistribution, the segmental and total gastrointestinal transit times (GItt) were measured in two litters of 10 and 15 day old Sprague Dawley rat pups using barium sulfate. Ten day old rat pups that remained with and without the dam had a total gastrointestinal transit time of 13.8 ± 0.9 hr and 9.3 ± 0.7 hr, respectively. This decrease (p<0.05) in total gastrointestinal transit time in the absence of the dam was age dependent, as it was not observed (p>0.05) in the 15 day old rat pup litter. The immunological impact of an exogenous sCD14 source was examined in human peripheral blood mononuclear cells (PBMC). Pre-treatment of CD14+ monocytes with sCD14 had a protective effect, one of reducing the production of proinflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) when challenged with LPS. 14C was absorbed by neonate rats upon ingestion of [14C]CD14 and exposure to relatively high concentrations of rCD14 led to a reduction in inflammation. This may be beneficial to initial gut colonization in breast-fed newborns. / Alexander Graham Bell NSERC CGS M scholarship. Japan Society for the Promotion of Sciences, Summer in Japan Fellowship. Funded by the Canadian Institutes of Health Research, Institute of Nutrition Metabolism and Diabetes Grant #82816 “Fate and function of breast milk and recombinant human CD14 at mammary and newborn gastrointestinal mucosal epithelia”.

Artemisinins are known for their low aqueous solubility and resultant poor and erratic absorption upon oral administration. The poor solubility and erratic absorption usually translate, to low bibavailability. Enzymatic degradation and physiological barriers are also amongst the challenges which must be overcome to ensure effective delivery. Artemisininbased monotherapy and combination therapies are essential for the management and treatment of uncomplicated as well as cerebral malaria. Artemisone and artemiside are novel artemisinin derivatives, their antimalarial activity/efficacy was evaluated in vitro and in vivo in the presence and absence of Pheroid™ technology. Pheroid™ technology is a patented drug delivery system which has the ability to capture, transport and deliver pharmacologically active compounds. Pharmacokinetic models were also constructed for artemis one and artemiside, both in the presence and absence of Pheroid™ technology. Results obtained with the jn vitro antimalarial activity evaluation indicated that artemiside was slightly more potent than artemisone and much more potent than artesunate. Artemiside had IC50 values of 0.54 ± 0.03 nM (reference) and 0.10 ± 0.05 nM (Pheroid™) (p = 0.009) while artemisone had values of 0.94 ± 0.04 nM (reference) and 0.21 ± 0.04 nM (Pheroid™) (p = 0.0001). Artesunate had IC50 values of 29.65 ± 0.05 nM (reference) and 10.20 ± 0.04 nM (Pheroid™) (p < 0.0001). Results obtained with the in vivo antimalarial activity evaluation indicated that artemisone led to more favourable treatment outcomes than artemiside. The Peters' 4-day suppressive test was used as a basis model. With artemisone treatment recrudescence occured at 16 days post infection at a dose of 20.0 mg/kg bodyweight and at 12 days post infection at 2.5 mg/kg bodyweight. With artemiside recrudescence occurred at 8 days post infection with both the 10.0 mg/kg and 2.5 mg/kg bodyweight treatment regimens. When comparing the antimalarial effect of the drugs with and without Pheroid™ technology there was no significant difference in terms of parasite reduction or in the achieved treatment outcomes of either compounds. The pharmacokinetic parameters were evaluated in a mouse model where C57 BL6 mice were used. The compounds were administered at a dose of 50.0 mg/kg bodyweight via an oral gavage tube at a volume of 200 µl. Blood samples were collected by means of tail bleeding. Sensitive and selective LC/MS/MS methods were developed to analyze the drug concentrations in the plasma samples. The relative bioavailability of artemisone was RA = 1.0 (reference) and RA = 4.57 (Pheroid™) (p < 0.001). The absolute bioavailability was calculated as F = 0.10 (reference) and F = 0.48(Pheroid™) (p < 0.001). The boiavailability of artemiside was not dramatically enhanced by the Pheroid™ delivery system. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

Ibogainas yra indolo grupės alkaloidas, išskiriamas iš augalo Tabernanthe iboga Baill. (Apocynaceae). Šis alkaloidas mažina priklausomybę nuo opiatų bei lengvina abstinencijos požymius. Noribogainas – ibogaino aktyvusis metabolitas, sukeliantis mažiau nepageidaujamų reiškinių. Darbo tikslas: ištirti ibogaino ir noribogaino toksiškumą ir farmakokinetines savybes taikant eksperimentinį laboratorinių pelių modelį. Uždaviniai: Nustatyti ibogaino ir noribogaino toksiškumą, apskaičiuojant šių medžiagų vidutinę mirtinąją dozę (LD50) laboratorinėms pelėms. Pritaikyti ir validuoti efektyviosios skysčių chromatografijos (ESC) metodiką ibogaino ir noribogaino analizei laboratorinių pelių kraujo plazmoje ir vidaus organuose. Išskirti ibogainą ir noribogainą iš laboratorinių pelių kraujo plazmos ir vidaus organų mėginių ir atlikti kiekybinį įvertinimą. Nustatyti ibogaino ir noribogaino farmakokinetinius parametrus pelių kraujo plazmoje ir organuose. Ištirti vienkartinės ir kartotinių ibogaino ir noribogaino dozių įtaką šių medžiagų kaupimuisi pelių organuose. Nustatyti farmakokinetiniai parametrai atskleidžia kiekybinius ibogaino ir noribogaino kitimus organizme, įtakojančius biologiškai aktyvios medžiagos veiksmingumą, o medžiagų kaupimasis pelių organuose padeda įvertinti toksinio poveikio riziką. Gauti tyrimų rezultatai naudingi ir informatyvūs siekiant toliau atlikti klinikinius tyrimus su žmonėmis. / Ibogaine is a psychoactive alkaloid extracted from the Tabernanthe Iboga Baill. (Apocynaceae). This alkaloid reduces dependence on opiates and attenuates withdrawal symptoms. Ibogaine is metabolized to metabolite – noribogaine. Noribogaine appears less likely to produce the adverse effects associated with ibogaine. The aim of work is to test the toxicity and pharmacokinetic properties of ibogaine and noribogaine by conducting tests with white laboratory mice. The objectives of the research work are as follows: To determine the toxicity of ibogaine and noribogaine by calculating the median lethal dose (LD50) in laboratory mice. To adapt and validate the methodology of high-performance liquid chromatography (HPLC) for the analysis of ibogaine and noribogaine in the blood plasma and internal organs of laboratory mice. To determine ibogaine and noribogaine in plasma and organs of mice. To determine pharmacokinetic parameters of ibogaine and noribogaine in mice blood plasma and organs. To test the influence of repeated doses of ibogaine and noribogaine on the accumulation of these substances in organs of mice. Pharmacokinetic properties reveal quantitative variation of ibogaine and noribogaine in the body, influencing the effectiveness of biologically active substances. Accumulation test of these substances helps to assess the risk of toxicity. The obtained results are useful and informative in order to continue to carry out clinical trials with humans.

The purpose of this study is the comparison of methods of image enhancement kinetics in breast MRI tomography, according to 4 models, that analyze dynamic image series. Specifically, the following models have been implemented: (a) the Kuhl empirical approach, (b) a 3-parameter empirical model, (c) the 3 parameter mathematical model of Jansen and (d) the 5-parameter mathematical model of Fan. These models have been tested in a classification task of breast lesions (benignity/malignancy), using a k-ΝΝ (k=3 and k=7) classifier. A case sample of 29 benign and 49 malignant lesions, originating from 1.5T system, were analyzed. A graphical user interface has been implemented, intended as a visual aid to guide the identification of the location of the analyzing Region of Interest (ROI) of the lesion. In this study, the enhancement kinetic features of the two empirical models, as well as the primary and the secondary kinetic features of the two mathematical models were calculated. For proper ROI selection, 2 feature maps (a) the initial enhancement and (b) the 3 Time Point (3TP) kinetic map (Hauth et al. 2006), were utilized as pre-processing step. To evaluate the classification performance, indices such as sensitivity, specificity and accuracy were utilized. Employing the initial enhancement map, classification performance obtained for Kuhl empirical approach (Kuhl et al. 1999), the 3-parameter empirical model, the mathematical model of Jansen et al (Jansen et al. 2008) and the mathematical model of Fan (Fan et al. 2004, 2007) was: (0.87, 0.34, 67.9%), (0.81, 0.65, 70.5%), (0.85, 0.55, 70.5%) and (0.81, 0.58, 67.9%), respectively. Classification results employing the 3TP kinetic map for the Kuhl empirical approach (Kuhl 1999), 3-parameter empirical model, the mathematical model of Jansen and the mathematical model of Fan were: (0.95, 0.58, 82.0%), (0.95, 0.82, 84.6%), (0.85, 0.68, 78.2%) and (0.93, 0.79, 79.4%), respectively. In conclusion, the 3TP kinetic contributed in the proper location of the analyzing ROI and subsequently in the improved classification of malignant from benign lesions for all enhancement kinetic models studied. / Σκοπός της παρούσας εργασίας είναι η σύγκριση μεταξύ μεθόδων ανάλυσης της κινητικής του σκιαγραφικού στην μαγνητική τομογραφία μαστού, σύμφωνα με 4 μοντέλα ανάλυσης που αξιοποιούν τα απεικονιστικά δεδομένα δυναμικών ακολουθιών εικόνων. Συγκεκριμένα, υλοποιήθηκαν: (α) η εμπειρική προσέγγιση Kuhl et al. (Kuhl et al. 1999), η οποία χρησιμοποιεί 1 ποσοτικό δείκτη της αρχικής ενίσχυσης του σήματος και ποιοτική εκτίμηση της κινητικής του σκιαγραφικού στη φάση έκπλυσης, (β) ένα εμπειρικό μοντέλο 3 ποσοτικών δεικτών που ποσοτικοποιούν την πρόσληψη και έκπλυση, (γ) το 3-παραμετρικό εμπειρικό μαθητικό φαρμακοκινητικό μοντέλο των Jansen et al. (Jansen 2008), (δ) το 5-παραμετρικό εμπειρικό φαρμακοκινητικό μαθητικό μοντέλο των Fan et al. (Fan et al. 2004, 2007), στα πλαίσια ταξινόμησης αλλοιώσεων του μαστού (καλοήθεια/κακοήθεια) με χρήση ταξινομητή k-ΝΝ (k=3 και k=7). Μελετήθηκαν 29 καλοήθεις και 49 κακοήθεις αλλοιώσεις, και οι λήψεις των εικόνων έγιναν από 1.5 T μαγνητικό τομογράφο. Υλοποιήθηκε γραφικό περιβάλλον διεπαφής (Graphical User Interface-GUI), προτεινόμενο ως εργαλείο υποβοήθησης για την επιλογή της τοποθέτησης της περιοχής ενδιαφέροντος για την αξιολόγηση των κινητικών χαρακτηριστικών της αλλοίωσης. Στα πλαίσια της παρούσας μελέτης, υπολογίστηκαν τα κινητικά χαρακτηριστικά για τα δύο εμπειρικά μοντέλα καθώς και τα πρωτεύοντα και δευτερεύοντα χαρακτηριστικά για τα μαθηματικά μοντέλα. Για την επιλογή της περιοχής ενδιαφέροντος υλοποιήθηκαν: (α) ένας κινητικός χάρτης πρώιμης ενίσχυσης σήματος, (β) ο κινητικός χάρτης 3TP (Hauth et al. 2006), οποίος εκφράζει τη συνολική κινητική του σκιαγραφικού. Για την αξιολόγηση της απόδοσης ταξινόμησης (διαφοροποίηση καλοήθειας/κακοήθειας) χρησιμοποιήθηκαν οι δείκτες ευαισθησία, ειδικότητα και ακρίβεια. Με χρήση του χάρτη πρώιμης ενίσχυσης για την επιλογή της περιοχής ενδιαφέροντος, η απόδοση ταξινόμησης, του εμπειρικού μοντέλου Kuhl et al. (1999), του εμπειρικού μοντέλου των 3 παραμέτρων, του μαθηματικού μοντέλου Jansen και του μαθηματικού μοντέλο Fan (Fan et al. 2004, 2007) ήταν: (0.87, 0.34, 67.9%), (0.81, 0.65, 70.5%), (0.85, 0.55, 70.5%) και (0.81, 0.58, 67.9%), αντιστοίχως. Με χρήση του κινητικού χάρτη 3TP η απόδοση ταξινόμησης του εμπειρικού μοντέλου Kuhl (Kuhl et al. 1999), του εμπειρικού μοντέλου των 3 παραμέτρων, του μαθηματικού φαρμακοκινητικού μοντέλου Jansen et al. (Jansen et al. 2008) και του μαθηματικού φαρμακοκινητικού μοντέλου Fan (Fan et al. 2004, 2007) ήταν: (0.95, 0.58, 82.0%), (0.95, 0.82, 84.6%), (0.85, 0.68, 78.2%) και (0.93, 0.79, 79.4%), αντιστοίχως. Συμπερασματικά, χρήση του κινητικού χάρτη 3TP συνεισφέρει σε ορθότερη επιλογή της θέσης της περιοχής ενδιαφέροντος προς ανάλυση, βελτιώνοντας αποτελέσματα της ταξινόμησης των κακοηθών από καλοήθεις αλλοιώσεις για όλα τα μοντέλα κινητικής σκιαγραφικού που μελετήθηκαν.

Orientador: José Ricardo de Arruda Miranda / Resumo: As nanopartículas magnéticas (NPMs) são uma classe de nanopartículas que se destacam em áreas da saúde, principalmente em aplicações teranósticas. O potencial das NPMs é prejudicado em função da absorção hepática, considerando que o fígado é uma rede complexa de células inter-relacionadas responsável pela captação do NPMs. Apesar de vários estudos concentrados na área, ainda é pouco compreendido como cada estrutura hepática opera no processo de retirada das NPMs da circulação sanguínea. As técnicas de imagem tem proporcionado avanços no entendimento de eventos fisiológicos, facilitando sua visualização. Atualmente, há uma gama de modalidades responsáveis pela detecção e imagiamento da biodistribuição das NPMs. Dentre essas técnicas de imagens, várias estão presentes apenas em hospitais ou em grandes centros de pesquisa. Esse trabalho tem como destaque, a aplicação de um novo método biomagnético, a Biosusceptometria AC (BAC), para a detecção in vivo de NPMs através de imagens. Fatores como ausência de radiação ionizante, versatilidade e alta resolução temporal são atributos do sistema frente às diversas técnicas de imagem. Neste estudo foi utilizado um novo arranjo do sistema, o sistema Multicanal BAC (ACB-MC), o qual permitiu a avaliação do processo de clearence das NPMs no sangue e seu posterior acúmulo no fígado em ratos Wistar. A partir das imagens dinâmicas obtidas e sua quantificação, foi proposto uma abordagem matemática a fim de auxiliar a farmacocinética de distribuiç... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Magnetic nanoparticles (MNPs) are widely used in healhty research areas, especially in terantic applications. The potential use of MNPS is diminished due to hepatic absorption, considering that the liver is a complex network of interrelated cells and the most responsible by MNPs uptake. Although there has been many studies in this area, it is still unknown how the liver removes MNPs from the bloodstream. Imaging techniques have provided more understanding of physiological events, enhancing their visualization. Currently, there is a range of modalities able to detect and image the biodistribution of MNPs. Among these techniques, several are restricted to large hospitals and research centers. In this work, our aim was to highlight the application of a new biomagnetic method, Biosusceptometry AC (BAC), for in vivo detection of MNPs through images. When compared to other systems, BAC has some advantages such as the absence of ionizing radiation, versatility and high temporal resolution. In this study, a new system arrangement, the Multicanal BAC system (ACB-MC) was used. This allowed the evaluation of the clearence process of MNPs in the blood and their subsequent accumulation in the liver. Those experiments were performed in Wistar rats. From the quantification of the dynamic images, a mathematical approach was proposed to investigate the pharmacokinetics of distribution and accumulation of MNPs. The ACB-MC system presented excellent temporal resolution and through sequential im... (Complete abstract click electronic access below) / Mestre

Objetivo: O objetivo do presente estudo foi descrever a relação entre as concentrações plasmáticas totais e livres tumorais do etoposídeo (ETO) e a inibição do crescimento do tumor observada em ratos Wistar portadores de tumor Walker- 256 (W256) utilizando a modelagem farmacocinética/farmacodinâmica (PK/PD). Métodos: Os procedimentos com animais foram aprovados no CEUA/UFRGS sob o número 22302. Os experimentos de farmacocinética foram realizados para determinar concentrações plasmáticas e livres em duas regiões do tumor sólido W256 através de microdiálise. Após a administração do ETO nas doses de 10 ou 20 mg/kg i.v. bolus em ratos Wistar portadores de tumor W256, amostras de sangue e microdialisado de tecido do centro e periferia do tumor foram coletadas simultaneamente, até 7 h pós-dose, para determinar o fator de penetração no tumor. Um método analítico por CLAE-UV foi desenvolvido e validado para quantificação do etoposídeo nas amostras de plasma e dialisado. Os experimentos de farmacodinâmica foram conduzidos em ratos portadores de tumor W256 que receberam ETO 5 e 10 mg/kg i.v. bolus uma vez ao dia por 8 e 4 dias, respectivamente. O volume dos tumores foram monitorados diariamente durante 30 dias. Análise não-compartimental dos dados de PK foi realizada no WinNonlin®. A modelagem dos dados PK e PK/PD foi realizada no Monolix®, utilizando abordagem populacional. Os dados PK/PD foram analisados usando o modelo Simeoni TGI modificado através da introdução de uma função Emax para descrever a relação nãolinear entre a concentração plasmática e tumoral e o efeito. Resultados e Discussão: O método por CLAE-UV foi desenvolvido e validado para quantificar as amostras de ETO em plasma e tecido. A penetração do ETO no tumor foi maior na periferia (61 ± 15 % e 61 ± 29 %) do que no centro do tumor (34 ± 6 % e 28 ± 11 %) após administração das doses 10 e 20 mg/kg, respectivamente (ANOVA, α = 0.05). Um modelo de 4 compartimentos compreendendo uma distribuição saturável (cinética de Michaelis-Menten) nos compartimentos tumorais a partir do compartimento central modelou simultaneamente os perfis de concentração-tempo do ETO em plasma e em ambas regiões do tumor. O modelo populacional PK/PD Simeoni TGI–Emax foi capaz de descrever o efeito antitumoral dependente do regime de administração do ETO utilizando concentrações totais plasmáticas ou livres no tumor, resultando em um maior k2max (potência máxima) para as concentrações livres (25,8 mL.μg-1.dia-1 - intratumoral vs. 12,6 mL.μg-1.dia-1 - plasma total). Conclusões: Os resultados mostram que a utilização das concentrações livres do fármaco no tumor para a modelagem PK/PD pode fornecer um melhor entendimento da relação farmacocinética e farmacodinâmica e melhoram a capacidade de previsão do modelo, considerando que a eficácia dos fármacos antineoplásicos no tratamento de tumores sólidos é dependente da capacidade do fármaco em se distribuir no tecido tumoral. / Objective: The aim of this study was to describe the relationship between total plasma and free interstitial tumor etoposide (ETO) concentrations and the drug tumor growth inhibition observed in a Walker-256 (W256) tumor-bearing Wistar rat model using the pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: The experiments with animals were approved by CEUA/UFRGS (protocol number 22302). Pharmacokinetic experiments were conducted to determine total plasma and free intratumoral concentrations in two regions of W256 solid tumor by microdialysis. After administration of ETO 10 or 20 mg/kg i.v. bolus to W256 tumorbearing Wistar rats, blood and tissue microdialysate samples from tumor center and periphery were simultaneously collected up to 7h to determine the tumor penetration factor. An analytical HPLC-UV method was developed and validated for quantification of ETO in plasma and microdialysate samples. The pharmacodynamic experiments were conducted in W256 tumor-bearing rats that received ETO 5 or 10 mg/kg i.v. bolus every day for 8 and 4 days, respectively. Tumor volumes were monitored daily for 30 days. Non-compartmental analysis of PK data was performed in WinNonlin®. The PK and PK/PD modeling by population approach were performed using Monolix®. PK/PD data were analyzed using a modification of Simeoni TGI model by introducing an Emax function to describe the nonlinear relationship between tumor and plasma concentrations and effect. Results and Discussion: The HLPCUV method was developed and validated to determine plasma and tissue samples of ETO. ETO tumor penetration was higher in the tumor periphery (61 ± 15 % and 61 ± 29 %) than center (34 ± 6 % and 28 ± 11 %) following 10 and 20 mg/kg doses, respectively (ANOVA, α = 0.05). A 4-compartment structural model comprising a saturable distribution (Michaelis-Menten kinetics) into the tumor compartments from the central compartment simultaneously described the ETO concentration–time profiles in plasma and both tumor regions. The PK/PD population Simeoni TGI–Emax model was capable of describing the schedule-dependent antitumor effects of ETO using total plasma or free tumor concentrations obtained in a W256-tumor bearing Wistar rat model, resulting in higher k2max (maximal potency) for free concentrations (25.8 mL.μg-1.day-1 - intratumoral vs. 12.6 mL.μg-1.day-1 total plasma). Conclusions: The results showed that the use of free intratumoral drug concentrations in the PK/PD modeling can provide a better understanding of the pharmacokinetics and pharmacodynamics relationship and improve the forecasting ability of the models considering that the efficacy of antineoplastic drugs in the treatment of solid tumors is dependent on the drug ability to distribute into the tumor.